Publications by authors named "Brian P Setchell"

10 Publications

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Obese father's metabolic state, adiposity, and reproductive capacity indicate son's reproductive health.

Fertil Steril 2014 Mar 11;101(3):865-73. Epub 2014 Jan 11.

Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, Robinson Institute, The University of Adelaide, Adelaide, South Australia, Australia; Repromed, Dulwich, South Australia, Australia.

Objective: To determine whether dietary and exercise regimes in obese males can provide a novel intervention window for improving the reproductive health of the next generation.

Design: Experimental animal study.

Setting: University research facilities.

Animal(s): C57BL6 male and female mice.

Intervention(s): Mice were fed a control diet (6% fat) or high-fat diet (21% fat) for 9 weeks. After the initial feeding, high-fat-diet males were allocated to diet and/or exercise interventions for a further 9 weeks. After intervention males were mated with females fed standard chow (4% fat) before and during pregnancy.

Main Outcome Measure(s): F1 sperm motility, count, morphology, capacitation, mitochondrial function, and sperm binding and weight of reproductive organs.

Result(s): Our primary finding was that diet intervention alone in founders improved offspring sperm motility and mitochondrial markers of sperm health (decreased reactive oxygen species and mitochondrial membrane potential), ultimately improving sperm binding. Sperm binding and capacitation was also improved in F1 males born to a combined diet and exercise intervention in founders. Founder sperm parameters and metabolic measures as a response to diet and/or exercise (i.e., lipid/glucose homeostasis, sperm count and morphology) correlated with offspring's sperm function, independent of founder treatment. This implicates paternal metabolic and reproductive status in predicting male offspring's reproductive function.

Conclusion(s): This is the first study to show that improvements to both metabolic (lipids, glucose and insulin sensitivity) and reproductive function (sperm motility and morphology) in obese fathers via diet and exercise interventions can improve subsequent reproductive health in offspring.
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http://dx.doi.org/10.1016/j.fertnstert.2013.12.007DOI Listing
March 2014

Improving metabolic health in obese male mice via diet and exercise restores embryo development and fetal growth.

PLoS One 2013 19;8(8):e71459. Epub 2013 Aug 19.

School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, South Australia, Australia.

Paternal obesity is now clearly associated with or causal of impaired embryo and fetal development and reduced pregnancy rates in humans and rodents. This appears to be a result of reduced blastocyst potential. Whether these adverse embryo and fetal outcomes can be ameliorated by interventions to reduce paternal obesity has not been established. Here, male mice fed a high fat diet (HFD) to induce obesity were used, to determine if early embryo and fetal development is improved by interventions of diet (CD) and/or exercise to reduce adiposity and improve metabolism. Exercise and to a lesser extent CD in obese males improved embryo development rates, with increased cell to cell contacts in the compacting embryo measured by E-cadherin in exercise interventions and subsequently, increased blastocyst trophectoderm (TE), inner cell mass (ICM) and epiblast cell numbers. Implantation rates and fetal development from resulting blastocysts were also improved by exercise in obese males. Additionally, all interventions to obese males increased fetal weight, with CD alone and exercise alone, also increasing fetal crown-rump length. Measures of embryo and fetal development correlated with paternal measures of glycaemia, insulin action and serum lipids regardless of paternal adiposity or intervention, suggesting a link between paternal metabolic health and subsequent embryo and fetal development. This is the first study to show that improvements to metabolic health of obese males through diet and exercise can improve embryo and fetal development, suggesting such interventions are likely to improve offspring health.
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http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0071459PLOS
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3747240PMC
April 2014

Diet and exercise in an obese mouse fed a high-fat diet improve metabolic health and reverse perturbed sperm function.

Am J Physiol Endocrinol Metab 2012 Apr 17;302(7):E768-80. Epub 2012 Jan 17.

School of Paediatrics and Reproductive Health, Discipline of Obstetrics and Gynaecology, University of Adelaide, South Australia, Australia.

Male obesity is associated with reduced sperm motility and morphology and increased sperm DNA damage and oxidative stress; however, the reversibility of these phenotypes has never been studied. Therefore, the aim of this study was to assess the reversibility of obesity and its associated sperm physiology and function in mice in response to weight loss through diet and exercise. C57BL6 male mice (n = 40) were fed either a control diet (CD; 6% fat) or a high-fat diet (HFD; 21% fat) for 10 wk before allocation to either diet and/or swimming exercise interventions for 8 wk. Diet alone reduced adiposity (1.6-fold) and serum cholesterol levels (1.7-fold, P < 0.05), while exercise alone did not alter these, but exercise plus diet also improved glucose tolerance (1.3-fold, P < 0.05). Diet and/or exercise improved sperm motility (1.2-fold) and morphology (1.1-fold, P < 0.05), and reduced sperm DNA damage (1.5-fold), reactive oxygen species (1.1-fold), and mitochondrial membrane potential (1.2-fold, P < 0.05) and increased sperm binding (1.4-fold) (P < 0.05). Sperm parameters were highly correlated with measures of glycemia, insulin action, and serum cholesterol (all P < 0.05) regardless of adiposity or intervention, suggesting a link between systemic metabolic status and sperm function. This is the first study to show that the abnormal sperm physiology resulting from obesity can be reversed through diet and exercise, even in the presence of ongoing obesity, suggesting that diet and lifestyle interventions could be a combined approach to target subfertility in overweight and obese men.
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http://dx.doi.org/10.1152/ajpendo.00401.2011DOI Listing
April 2012

An accidental andrologist.

Authors:
Brian P Setchell

Biol Reprod 2012 Mar 22;86(3):79. Epub 2012 Mar 22.

School of Medical Sciences, University of Adelaide, Adelaide, South Australia, Australia.

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http://dx.doi.org/10.1095/biolreprod.111.097907DOI Listing
March 2012

SIRT6 in mouse spermatogenesis is modulated by diet-induced obesity.

Reprod Fertil Dev 2011 ;23(7):929-39

Discipline of Obstetrics and Gynaecology, School of Paediatrics and Reproductive Health, University of Adelaide, Adelaide, SA 5005, Australia.

Male obesity is associated with reduced sperm function and increased incidence of sperm DNA damage; however, the underlying molecular mechanisms have not yet been identified. Mammalian SIRT6 protein is involved in caloric-dependant DNA damage repair in other tissue types, yet a possible role for SIRT6 in male obesity and subfertility has not been investigated previously. To assess SIRT6 levels and activity in the testes, male mice (n=12 per diet) were fed either a control diet (CD; 6% fat) or a high-fat diet (HFD; 21% fat) for 16 weeks before the collection of testes and spermatozoa. SIRT6 protein was localised to the nucleus of transitional spermatids and the acrosome of mature spermatozoa, with levels significantly decreased in HFD-fed male mice (P<0.05). This decrease in SIRT6 protein was associated with transitional spermatids having increased levels of acetylated H3K9 in the nucleus (P<0.01) and increased DNA damage (P<0.001). We propose a role for SIRT6 in spermiogenesis and potentially protamination processes, which are known to be compromised by male obesity.
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http://dx.doi.org/10.1071/RD10326DOI Listing
January 2012

Whole-body heat exposure induces membrane changes in spermatozoa from the cauda epididymidis of laboratory mice.

Asian J Androl 2010 Jul 7;12(4):591-8. Epub 2010 Jun 7.

Discipline of Anatomy and Pathology, School of Medical Sciences, Faculty of Health Sciences, University of Adelaide, Adelaide, South Australia, Australia.

This study was carried out to determine if exposure to hot environmental temperatures had a direct, detrimental effect on sperm quality. For this the effect of whole-body heat exposure on epididymal spermatozoa of laboratory mice was investigated. C57BL/6 mice (n = 7) were housed in a microclimate chamber at 37 degrees C-38 degrees C for 8 h per day for three consecutive days, while control mice (n = 7) were kept at 23 degrees C-24 degrees C. Cauda epididymal spermatozoa were obtained 16 h after the last heat treatment. The results showed that sperm numbers were similar in the two groups (P = 0.23), but after heat treatment, a significant reduction in the percentage of motile sperm was present (P < 0.0001). Membrane changes of the spermatozoa were investigated by staining with phycoerythrin (PE)-conjugated Annexin V, which detects exteriorization of phosphotidylserine from the inner to the outer leaflet of the sperm plasma membrane, and 7-aminoactinomycin D (7-AAD), which binds to the sperm nucleus when the plasma membrane is damaged. The percentage of spermatozoa showing positive staining with Annexin V-PE or 7-AAD or both, was significantly higher (P < 0.05) in heat-exposed mice compared with controls. These results show that whole-body heat exposure to 37 degrees C-38 degrees C induces membrane changes in the epididymal spermatozoa of mice, which may lead to apoptosis.
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http://dx.doi.org/10.1038/aja.2010.41DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3739373PMC
July 2010

Blood-testis barrier, junctional and transport proteins and spermatogenesis.

Authors:
Brian P Setchell

Adv Exp Med Biol 2008 ;636:212-33

Department of Anatomical Sciences, University of Adelaide, Adelaide, Australia.

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http://dx.doi.org/10.1007/978-0-387-09597-4_12DOI Listing
January 2010

Interleukin-18 is expressed in rat testis and may promote germ cell growth.

Mol Cell Endocrinol 2005 Aug;240(1-2):64-73

Department of Woman and Child Health, Paediatric Endocrinology Unit Q2:08, Astrid Lindgren Children's Hospital, Karolinska Institute and University Hospital, Stockholm, Sweden.

Although host-defence mechanisms, designed to preserve the integrity of the developing germ cells are operative in the testis, the components of this protective system have yet to be characterised in detail. Here, we report that the cytokine interleukin-18 (IL-18) is expressed in the rat testis and may contribute to these defences. Thus, analysis by RT-PCR and Western blotting revealed pronounced testicular expression of pro-IL-18 from postnatal day 5 and onwards. Expression of both IL-18 mRNA and protein was found to be localised to meiotic and post-meiotic germ cells as evaluated by in situ hybridisation and immunohistochemistry, respectively. The mRNA species coding for the IL-18 receptor and IL-1beta converting enzyme, which activates pro-IL-18, were also shown to be expressed by the seminiferous tubules. Recombinant IL-18 was seen to stimulate spermatogonial DNA synthesis in cultures of staged segments of rat seminiferous tubules, without influencing germ cell apoptosis. These results suggest that IL-18 may have host-protective and growth-promoting functions in the testis, but further investigations need to be done to confirm this.
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http://dx.doi.org/10.1016/j.mce.2005.05.011DOI Listing
August 2005

The recycling of carbon in glucose, lactate and alanine in sheep.

J Comp Physiol B 2005 Aug 30;175(6):413-22. Epub 2005 Jun 30.

Biochemistry Department, AFRC Institute of Animal Physiology (now The Babraham Institute), Cambridge, CB2 4AT, UK.

Pregnant ewes with catheters implanted in an artery and the uterine and recurrent tarsal veins were infused at a constant rate with U-(14)C-labelled glucose, alanine or bicarbonate. Measurements were made of the overall and local fractional contribution of glucose and alanine to CO(2) production and of the extent of interconversion of these metabolites. In the whole animal, by coupling the results with the authors' previous study of lactate metabolism, a solution was obtained to an open unrestricted 4-compartment model of the exchange of carbon between glucose, lactate, alanine and CO(2). A more limited study was made with non-pregnant sheep because complete data for lactate interactions with alanine were not available. Our analysis of glucose/lactate/alanine/CO(2) interactions in pregnant sheep suggests that about two-thirds of the glycogenic carbon was oxidised fairly directly to CO(2). There was relatively little recycling of glucose carbon through lactate and alanine so that most of the remaining glycogenic carbon was stored as product with relatively long turnover time. It is possible that much of this was in the form of muscle glycogen, and analysis of glycogenic carbon exchange across the hind limb muscle was consistent with this conclusion. In non-pregnant ewes, the findings, although incomplete, suggested that there were no great differences from the findings in pregnant ewes.
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http://dx.doi.org/10.1007/s00360-005-0003-5DOI Listing
August 2005

Production and secretion of interleukin-1alpha proteins by rat testis.

Biochem Biophys Res Commun 2002 Sep;297(3):492-7

Pediatric Endocrinology Unit, Q2: 08, Department of Woman and Child Health, Astrid Lindgren Children's Hospital, SE-171 76 Stockholm, Sweden.

The present study characterizes constitutively expressed rat testicular interleukin-1alpha (IL-1alpha) proteins. IL-1 bioactivity of crude testis protein was completely neutralized by IL-1alpha antiserum, IL-1 receptor antagonist, and soluble type I IL-1 receptor. Upon non-denaturating gel permeation chromatography, bioactive IL-1 eluted at molecular sizes of 45, 31, and 17kDa and at charges of pH 5.7 and 6.0 after chromatofocusing. SDS-PAGE/Western blot analysis of proteins extracted from whole testis, seminiferous tubules, interstitial, and seminiferous tubule fluids all demonstrated IL-1alpha immunoreactivity at 45, 24, and 19kDa. Activated macrophages and tissue proteins from endotoxin treated rats showed immunoreactive 31 and 19kDa IL-1alpha. The results indicate that the testis produces three isoforms of IL-1alpha proteins that are secreted into the interstitial compartment and tubular lumen where they may exert paracrine functions. The testicular IL-1alpha isoforms may represent posttranslationally modified precursor, mature IL-1alpha, and a 24-kDa alternate splice form.
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http://dx.doi.org/10.1016/s0006-291x(02)02239-8DOI Listing
September 2002
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